5-phenyl-2-piperidones and 5-phenyl-2-thiopiperidones in compositions and methods for treating pain, fever and inflammation

ABSTRACT

Novel 5-phenyl-2-piperidone and 5-phenyl-2-thiopiperidone compounds and the processes for preparing the same are disclosed. In addition the invention concerns piperidones and thiopiperidones which exhibit anti-inflammatory properties and also possess an effective degree of anti-pyretic and analgesic activity.

United States Patent 1 Shen et al.

[ 1 Feb. 27, 1973 S-PHENYL-Z-PIPERIDONES AND 5- PHENYL-Z-THIOPIPERIDONESIN COMPOSITIONS AND METHODS FOR TREATING PAIN, FEVER AND INFLAMMATIONInventors: Tsung-Ying Shen; Bruce E. Witzel,

both of Westfield, NJ.

Assignee: Merck & Co., Inc., Rahway, NJ.

Filed: Nov. 19, 1970 Appl. No.: 91,175

Related U.S. Application Data Continuation-impart of Ser. No. 808,660,March 19, 1969, abandoned.

U.S. Cl ..424/267, 260/293.8 Int. Cl. ..A61k 27/00 Field of Search..424/267; 260/293.8

References Cited OTHER PUBLICATIONS Hill et al. J.A.C.S. Vol. 66, pp.737739 (1959).

Primary Examiner-Standley J. Friedman Attorney-Julian S. Levitt, HarryE. Westlake, Jr. and I. Louis Wolk [57] ABSTRACT 20 Claims, No DrawingsS-I'HENYL-It-PllPERIIDONEfi AND S-IP'HENYL-Z- THIOIPIPEWDONEB llNCOMPUSETIONS AND METHODS FOR TREATKNG PAW, FEVER AND KNFLAMMATHON Thisapplication is a continuation-in-part of U.S. application Ser. No.808,660, filed Mar. 19, 1969, now abandoned.

This invention relates to a novel class of -phenyl-2- piperidones andthiopiperidones and derivatives thereof which are useful in thetreatment of inflammation and which also exhibit potent analgesic andantipyretic activity. The invention further relates to pharmaceuticalcompositions containing said materials and methods of treatinginflammation, pain and fever.

The present invention embraces the novel compounds having the structuralformulas as shown in FIGS. Ia and lb:

where R is hydrogen, alkyl (preferably lower alkyl such as methyl,ethyl, propyl, etc.), alkenyl (preferably lower alkenyl such as vinyl,allyl, methallyl, etc.), alkynyl (preferably lower alkynyl such asethynyl, methylbutynyl, etc.), aralkenyl (preferably arloweralkenyl suchas phenylpropylenyl, phenylbutylenyl, etc.), aryl (preferably phenyl) orsubstituted phenyl (such as tolyl, halophenyl, anisyl, etc.), aralkyl(preferably arloweralkyl such as benzyl, phenethyl, etc.), acyl (such asacetyl, propionyl, benzoyl, etc.) and dialkylaminoalkyl (preferablydiloweralkylaminolower alkyl, such as diethylaminoethyl, etc.);

W is hydrogen, halogen (such as fluoro, chloro,

bromo, etc.), halo alkyl (such as CF amino, dialkylamino (preferablydiloweralkylamino such as dimethylamino, diethylamino, methylethylamino,etc.), dialkylaminoalkyl (preferably diloweralkylaminoloweralkyl such asdimethylaminomethyl, diethylaminomethyl, etc.), carboalkoxyalkyl(preferably carboloweralkoxylowerallcyl such as carbomethoxyrnethyl,carboethoxymethyl, etc.) and hydroxy; W can be substituted at the 3, 4,5 or 6-positions; and g X and Y are each hydrogen, alkyl (preferablyloweralkyl such as methyl, ethyl, propyl, etc.), halogen (such asfluoro, chloro, bromo, etc.), haloalkyl (preferably haloloweralkyl suchas fluoromethyl, trichloromethyl, trifluoromethyl, etc.), aryl(preferably phenyl, naphthyl, substituted phenyl, such as tolyl,halophenyl, alkoxyphenyl, etc.), nitro, amino, acylamino (such asacetylamino, etc.), acyl (such as acetyl, propionyl, benzoyl, etc.),carboxy, carboalkoxy (preferably carboloweralkoxy such as carbomethoxy,carboethoxy, etc.), carbamyl, dialkylsulfamyl (preferablydilowerallcylsulfamyl such as dimethylsulfamyl), alkylamino (preferablyloweralkylamino such as methylamino, ethylamino, etc.), and dialkylamino(preferably diloweralkylamino such as dimethylamino, diethylamino,etc.), alkyl- 5 mercapto (preferably loweralkylmercapto, such asmethylmercapto, etc.), alkylsulfmyl (preferably loweralkylsulfmyl, suchas methylsulfinyl, etc.), alkylsulfonyl (preferably loweralkylsulfonyl,such as methylsulfonyl, etc.); X and Y can be substituted at the 2, 3,4, 5 and o-positions; with the proviso that W, X, Y and R must not beall hydrogen at the same time, and when R is alkyl, W, X or Y must beother than hydrogen and when W is halogen, dialkylamino ordialkylaminoalkyl, R, X or Y must be other than hydrogen.

in its more preferred aspects, this invention relates to the class ofchemical compounds having the structural formulas as shown in FIGS. Iaand lb where R is hydrogen; W is hydrogen or halogen; and X and Y arehydrogen, halogen, haloalkyl, nitro, alkylamino and alkyl.

The invention further relates to 5-phenyl-2- piperidones andthiopiperidones as represented by Formulas Ila and [lb which are usefulin the treatment of inflammation, pain and fever and are components ofpharmaceutical compositions that are utilized in such treatment:

X Y Xt/ Y 0 as r r R R Ila III) where R is hydrogen, alkyl (preferablylower alkyl such as methyl, ethyl, propyl, etc.), alkenyl (preferablylower alkenyl such as vinyl, allyl, methallyl, etc.), alkynyl(preferably lower alkynyl such as ethynyl, methylbutynyl, etc.), aralkyl(preferably arloweralkyl such as benzyl, phenethyl, etc.), aralkenyl(preferably arloweralkenyl such as phenylpropylenyl, phenylbutylenyl,etc.), aryl (preferably phenyl) or substituted phenyl (such as tolyl,halophenyl, anisyl, etc. acyl (such as acetyl, propionyl, benzoyl, etc.)and dialkylaminoalkyl (preferably diloweralkylaminolower alkyl, such asdiethylaminoethyl, etc.

W is hydrogen, halogen (such as fluoro, chloro, bromo, etc.), halo alkyl(such as CF alkyl (preferably lower alkyl such as methyl, ethyl, propyl,etc.), amino, dialkylamino (preferably diloweralkylamino such asdimethylamino, diethylamino, methylethylamino, etc.), dialkylaminoalkyl(preferably diloweralkylaminoloweralkyl such as dimethylaminomethyl,diethylaminomethyl, etc.), aryl (preferably phenyl or substitutedphenyl), carboalkoxy (preferably carboloweralkoxy such as carbomethoxy,car boethoxy, etc.), carboalkoxyalkyl (preferablycarboloweralkoxyloweralkyl such as carbomethoxymethyl,carboethoxymethyl, etc.), and hydroxy; W can be substituted at the 3, 4,5 or 6-positions; and

X and Y are each hydrogen, alkyl (preferably loweralkyl such as methyl,ethyl, propyl, etc.), halogen (such as fluoro, chloro, bromo, etc.),hydroxy, alkoxy (preferably lower alkoxy such as methoxy, ethoxy,propoxy, etc.), haloalkyl (preferably haloloweralkyl such asfluoromethyl, trichloromethyl, trifluoromethyl, etc.), aryl (preferablyphenyl, naphthyl, substituted phenyl, such as tolyl, halophenyl,alkoxyphenyl, etc.), nitro, amino, acylamino (such as acetylamino,etc.), acyl (such as acetyl, propionyl, benzoyl, etc.), carboxy,carboalkoxy (preferably carboloweralkoxy such as carbomethoxy,carboethoxy, etc.), carbamyl, dialkylsulfamyl (preferablydiloweralkylsulfamyl such as dimethylsulfamyl), alkylamino (preferablyloweralkylamino such as methylamino, ethylamino, etc.) and dialkylamino(preferably diloweralkylamino such as dimethylamino, diethylamino,etc.), alkylmercapto (preferably loweralkylmercapto, such asmethylmercapto, etc.), alkylsulfinyl (preferably loweralkylsulfinyl,such as methylsulfinyl, etc.), alkylsulfonyl (preferablyloweralkylsulfonyl, such as methylsulfonyl, etc.); X and Y can besubstituted at the 2, 3, 4, 5 and 6-positions.

In its more preferred aspects, this invention relates to the class ofchemical compounds having the structural formulas as shown in FIGS. Ilaand Rh where R is hydrogen; W is hydrogen, halogen or alkyl; and X and Yare hydrogen, halogen, alkoxy, haloalkyl, nitro, alkylamino and alkyl.

Representative compounds of this invention are as follows:

5-(p-nitrophenyl)-2-piperidone S-(p-chlorophenyl)-2-piperidone5-(o-chlorophenyl)-2-thiopiperidone 5-(o-tolyl)-2-piperidone5-(o-tolyl)-2-thiopiperidone S-(p-fluorophenyl)-2-piperidone5-(p-fluorophenyl)-2-thiopiperidone S-(p-aminophenyl)-2-piperidone5-(m-chlorophenyl)-5-carboethoxy-2-piperidone5-(p-methoxyphenyl)-2-piperidone 5-(o,o'-dichlorophenyl)-2-piperidoneS-(p-methoxyphenyl)-3-methyl-1-acetyl-2- thiopiperidoneS-(p-nitrophenyl-l-benzyl-2-piperidoneS-(p-biphenylyl)-5-methyl-2-thiopiperidone 5 -phenyl-l-acetyl-2-piperidone 5-phenyl-3-chloro-l-methyl-2-thiopiperidone.

The piperidones and thiopiperidones of the invention possess a highdegree of anti-inflammatory, analgesic and antipyretic activity. Theyare of value in the treatment of arthritic and dermatological disordersor like conditions responsive to anti-inflammatory drugs. In generalthey are indicated for a wide variety of conditions where one or more ofthe symptoms of inflamation, fever and pain are manifested. Exemplary ofsuch conditions are rheumatic diseases, for example, rheumatoidarthritis, osteoarthritis, and other degenerative joint diseases,psoriatic arthritis, ankylosing spondylitis, gout, and rheumatic fever;soft-tissue rheumatism, for

example, tendinitis, periarthritis, and periostitis; acute muscularrheumatism, for example, sciatica and the like; treatment of pain afterfractures, pain and inflammation associated with dental surgery, and thelike, human and veterinary disease conditions exhibiting the foregoingsymptoms requiring the use of an anti-inflammatory, analgesic and/oranti-pyretic pharmaceutical composition.

For these purposes the compounds of the invention may be administeredorally, topically, parenterally, by inhalation spray or rectally informulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrastemal injection or infusion techniques. In addition to thetreatment of warmblooded animals such as mice, rats, horses, dogs, cats,etc., the compounds of the invention are effective in the treatment ofhumans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in orderto provide a pharmaceutically elegant andpalatable preparation. Tablets contain the active ingredient inadmixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be,for example, inert diluents, such as calcium carbonate, sodiumcarbonate, lactose, calcium phosphate or sodium phosphate; granulatingand disintegrating agents, for example, maize starch, or alginic acid;binding agents, for example starch, gelatine or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or tale. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearateabove or with a wax may be employed.

Formulations for oral use may also be presented as hard gelatinecapsules wherein the active ingredient is mixed with an inert soliddiluent, for example, calcium carbonate, calcium phosphate or kaolin, oras soft gelatine capsules wherein the active ingredient is mixed withwater or an oil medium, for example arachis oil, peanut oil, liquidparaffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or con- The term unitdosage form" as used in the specification and claims refers tophysically discrete units suitable as unitary dosages for human subjectsand animals, each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect inassociation with the required pharmaceutical diluent, carrier orvehicle. The specifications for the novel unit dosage forms of thisinvention are dictated by and directly dependent on (a) the uniquecharacteristics of the active material and the particular therapeuticeffect to be achieved, and (b) the limitations inherent in the art ofcompounding such active material for therapeutic use in humans andanimals, as disclosed in detail in this specification, these beingfeatures of the present invention. Examples of suitable unit dosageforms in accord with this invention are tablets, capsules, pills,troches, powder packets, granules, wafers, cachets, segregated multiplesof any of the foregoing, and other forms as herein described.

lt will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy. In general, the dosageregimen in carrying out the methods of this invention is that whichinsures maximum therapeutic response until improvement is obtained andthereafter is the minimum effective level which continues to providerelief.

The 5-phenyl-2-piperidones and 5-phenyl-2- thiopiperidones of thisinvention are conveniently prepared by the following methods.

When an acrylic acid ester or a substituted acrylate is condensed usingMichael reaction conditions with a benzyl or substituted benzyl cyanide,the corresponding 'y-cyano-y-phenyl butyrate (IV) is formed. Catalyticreduction of the nitrile affords the A-amino phenyl valerate (III) whichrapidly undergoes intermolecular reaction with the ester group to obtainthe desired S-phenyI-Z-piperidones (Ila); activation of the l-nitrogenfollowed by treatment with an alkylating or acylating agent results inN-substituted 5-phenyl-2- piperidones (la).

When the synthesis of products with various substituents is desired, theMichael condensation is carried out with the appropriately substitutedstarting materials. Thus, if the 5-(p-chlorophenyl)-3-methyl-2-piperidone is desired, the Michael reaction would commence with a-methylacrylate and p-chloro-benzyl cyanide.

The following reaction equations illustrate this method of preparation:

X lv-CHJCN w pi ON c=o kw Y w NH: l

here W, X, Y and R are as defined above and R is alkyl or aralkyl.

a. The Michael condensation is carried out in a suitable solvent(preferably a polar solvent, such as ethanol, dioxane, dimethoxyethane,etc.) in the presence of a strong base such as sodium alkoxide, tritonB, etc.

b. Reduction of the nitrile is carried out catalytically in a polarsolvent. It is preferable to use Raney nickel in an alcohol underSOD-3,000 p.s.i.

c. Upon heating the reduction product between 30 and 125C. ring closuretakes place.

d. Reacting with a strong base such as sodium hydride in an inertatmosphere activates the l-nitrogen. Addition of an alkylating oracylating agent, such as an aliphatic tosylate or halide or an alkanoicacid anhydride or halide, or a benzoyl halide results in the N-substituted products.

A further method of preparation involves the reduction of thecorresponding S-phenyI-Z-pyridone compounds. When a 5-amino-2-halopyridine is diazotized in the presence of benzene or a substitutedbenzene compound, the corresponding 5-phenyl-2-halo pyridine (V1) isformed which upon hydrolysis gives the 5-phenyl-2-[lH]-pyridones (V)selective reduction of the pyridine ring results in the formation of5-phenyl-2- piperidone compounds (ll) which can then be alkylated oracylated as above to prepare the desired N-substituted-S-phenyl-2-piperidone (1) products. The following reactionequation illustrates this method of preparation:

HQN- m A Y L x- -Y Q) Ki w N VI fl s 1%. I X v Y w I Y w TII H v IIAdensation products of ethylene oxide with long chain aliphatic alcohols,for example heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol mono-oleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyoxyethylene sorbitanmono-oleate. The said aqueous suspensions may also contain one or morepreservatives, for example ethyl, or n-propyl, p-hydroxy benzoate, oneor more coloring agents, one or more flavoring agents, and one or moresweetening agents, such as sucrose, saccharin, or sodium or calciumcyclamate.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oils, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally occurring gums, for example gum acacia or gum tragacanth,naturally occurring phosphatides, for example soya bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan mono-ole'ate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan mono-oleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, sorbitol or sucrose. Such formulations may also contain ademulcent, a preservative and flavoring and coloring agents.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example as a sterile injectable aqueous oroleagenous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1:3-butane diol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic monoordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectibles.

For parenteral administration aqueous fluid unit dosage forms can beprepared. In preparing the parenteral form, a measured amount of activeingredient is placed in a vial, and the vial and its contents aresterilized and sealed. An accompanying vial of sterile water is providedas a vehicle to form a suspension prior to administration.Advantageously, the sterile water can have dissolved therein a localanesthetic and a buffering agent. Parenteral aqueous solutions can bemade by preparing a suitable pharmaceutically-acceptable salt of theactive ingredient such as the acetate, citrate, tartrate, maleate,lactate and the like.

Alternatively, a parenteral suspension can be prepared by suspending theactive ingredient in a parenterally acceptable vegetable oil with orwithout additional adjuvants, and sterilizing after filling into vials.

For veterinary oral use the active ingredient is conveniently preparedin the form of a food premix. The food premix can comprise the activeingredient in admixture with an edible pharmaceutical diluent of thetype previously mentioned such as starch, oatmeal, flour, calciumcarbonate, talc, dried fish meal, and the like. The prepared premix isthen conveniently added to the regular feed, thereby providingmedication to the animal in the course of feeding.

The compounds of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are cocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensionsetc. containing the anti-inflammatory agents are employed.

Dosage levels of the order of 0.5 to 100 mg. per kilogram of body weightper day are useful in the treatment of the above indicated conditions.Accordingly, inflammation is effectively treated and anti-pyretic andanalgesic activity manifested by the administration from about 0.5 to100 milligrams of the compound per kilogram of body weight per day.Advantageously oral administration of from about 2 mg. to about 50 mg.per kilogram of body weight and especially from about 4 mg. to about 20mg./kg. per daily dosage produce highly effective results. Comparativedosages are used in parenteral, rectal and topical administration.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration of humans may containfrom 5 mg. to 5 grams of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout percent of the total composition. Dosage unit forms will generallycontain between from about 25 mg. to about 500 mg. of active ingredient.

e. The diazotization of the 2-chloro-5-amino pyridines is carried outwith or without an inert solvent in the presence of amyl nitrite and thesubstituted benzene with heating. Other nitrosating agents may be usedin place of amyl nitrite.

f. Hydrolysis of 2-halo pyridine compounds can be carried out in thepresence of a strong base or by the use of a metal acetate in aceticacid.

g. Selective catalytic reduction of the pyridone ring with a metalcatalyst in the presence of hydrogen gives the 5-phenyl-2-piperidones.

h. Reacting with a strong base such as sodium hydride in an inertatmosphere activates the l-nitrogen. Addition of an alkylating oracylating agent such as an aliphatic tosylate or halide or an alkanoicacid anhydride or halide, or a benzoyl halide results in the N-substituted products.

The 5-phenyl-2-thiopiperidone (lb) of this invention can be preparedfrom the corresponding 5-phenyl-2- piperidones by heating with P 8 Thereaction can be carried out either on those compounds which areunsubstituted at the l-position (Ila) which can then be l-alkylated orl-acylated to the desired compounds (lb), or the products can beprepared from those compounds which are already substituted at thel-position (la). These reactions are represented by the followingequations:

W K w -O l I?) H l 1'1 11a 1 X-Y X /O\ Y W w 3 \N S i In Appropriatelydesired end products having various W, X and Y substituents can beprepared at various stages of the synthesis using suitable reactions inorder to convert one group to another, thus, for example, usingconventional methods, a halogen group can be treated under Rosenmund VonBraun conditions to the nitrile compound which in turn can be hydrolyzedto a carboxy. A nitro can be reduced to an amino group and a hydroxycompound can be prepared by demethylation of a methoxy substituent.Mercapto groups can be prepared from conventional diazotizationtechniques.

The starting materials of this invention, namely, the benzyl-cyanidesand 2'halo-5-amino pyridines are well known in the art.

The intermediate compounds of this invention are not only useful inpreparing the end products of this in vention but do themselves exhibitanti-inflammatory activity and are therefore useful in the treatment ofthe same disorders.

The following are a group of detailed examples which show thepreparation of desired compounds of this invention. They are to beconstrued as illustrations of the invention and not as limitationsthereof.

EXAMPLE 1 Methyl 'y-cyano"y p-chlorophenyl) butyrate To 9] g. ofp-chlorobenzyl cyanide and 6 ml. of Triton B in 360 ml. of dioxane isadded 38.7 g. of methyl acrylate over an 80 minute period, while keepingthe temperature below 40C. The reaction mixture is then cooled to roomtemperature, allowed to stir for 15 hours, and concentrated to aresidue. The crude product is partition separated with 800 ml. of ether,30 drops of acetic acid and 300 ml. of water. The ether layer is washedwith water, dried over sodium sulfate, and distilled to obtain methyl-y-cyano-'y-(pchlorophenyl)-butyrate (b. p. l173C./3 mm).

EXAMPLE la When an equimolar amount of the nitriles of Table I below aresubstituted for p-chlorobenzyl cyanide in the procedure of Example 1,the corresponding 'y-cyano-y- (substituted phenyl) butyrate of Table IIbelow is obtained.

TABLE I benzyl cyanide p-fluorobenzyl cyanide o-fluorobenzyl cyanidem-fluorobenzyl cyanide o-chlorobenzyl cyanidem-chloro-(a-carboethoxy)-benzyl cyanide p-methoxybenzyl cyanideo-methoxybenzyl cyanide m-methoxybenzyl cyanide p-trifluoromethylbenzylcyanide p-dimethylaminobenzyl cyanide p-methylaminobenzyl cyanidep-phenyl-a-methyl benzyl cyanide p-nitrobenzyl cyanide a-naphthylmethylcyanide B-naphthylmethyl cyanide o-methylbenzyl cyanide m-methylbenzylcyanide p-methylbenzyl cyanide 2,6-dichlorobenzyl cyanidepentafluorobenzyl cyanide p-acetylbenzyl cyanide p-carbomethoxy-aphenylbenzyl cyanide p-acetamidobenzyl cyanide p-dimethylsulfamylbenzylcyanide 2-methyl-4-chlorobenzyl cyanide 3 ,4-dimethoxybenzyl cyanideTABLE ll methyl 'y-cyano-y-phenylbutyrate methyl'y-cyano-7-(p-fluorophenyl)butyrate methyl'y-cyano-y-(o-fluorophenyl)butyrate methyl 'y-cyanoy-(m-fluorophenyDbutyrate methyl y-cyano-y-p-dim ethylsulfamylphenyl)butyrate methyl y-cyano-'y-(2-methyl-4-chlorophenyl )butyrate methyly-cyano-y-( 3 ,4-dimethoxyphenyl)butyrate EXAMPLE lb When an equimolaramount of the substituted acrylates of Table III below is used in theprocedure of Example 1 with the desired nitrile of Table I, Example la,the corresponding 'y-cyano-y-(substituted phenyl) substituted butyrateis formed. A representative list of these products is shown in Table IVbelow.

TABLE III methyl a-methyl acrylate ethyl a-methyl acrylate methyla,B-dimethyl acrylate methyl a-dimethylaminoacrylate ethyla-dimethylaminoethylacrylate methyl oz-phenylacrylate methyla-phenylacrylate methyl crotonate TABLE IV methyla-methyl-'y-cyano-y-phenylbutyrate methyla-methyl-y-cyano-y-(o-methylphenyl)butyrate methyla-methyl-y-cyano--y-(p-chlorphenyl)butyrate methyla-methyl-y-eyano-y-(2,6-dichlorophenyl)butyrate methyla,fi-dimethyl-y-cyano-y-(o-methylphenyl)butyrate methyla-dimethylamino-y-cyano-y-phenylbutyrate ethyla-dimethylaminoethyl-y-cyano-y-phenylbutyrate methylB-phenyl-y-cyano-y-(o-methylphenyl)butyrate methyla-phenyl-y-cyano-y-(o-methylphenyl)butyrate methyla-methyl-y-cyano-y-(p-nitrophenyl)butyrate benzylafi-dimethyl-y-cyano-y-(p-chlorophenyl)butyrate benzyla,B-dimethyl-'y-cyano-'y-(o-methylphenyl)butyratemethyla-methyl-'y-cyano-y-(2,6-dichlorophenyl)butyrate methyl tyratea-methyl-y-cyano-y-(p-methoxyphenyl)bumethyla-methyl-y-cyano-y-(Z-methyl-4- chlorophenyl)-butyrate benzyla,B-dimethyl-'y-cyano-y-(p-biphenylyl)butyrate benzyla,fidimethyl-y-cyano-y-(o-chlorophenyl)butyrate methyla-methyl-y-cyano-y-( 3 ,4-dimethoxyphenyl)butyrate EXAMPLE 2 5-(p-Chlorophenyl )-2-piperidonc Methyl A-amino-y-(p-chlorophenyl)-vulcrutc To 119 g. of methyl y-cyano-y-(p-chlorophenyl)butyrate and lg. of platinum oxide, is added 40 ml. of glacial acetic acid. This isagitated at room temperature under 40 p.s.i. in a hydrogen atmosphere.The reaction mixture is filtered and concentrated in vacuo to acolorless oil.

5-(p-Chlorophenyl)J-piperidone To the residue from the above step isadded ml. of xylene and the reaction mixture is refluxed for 20 hours.This is then allowed to cool, filtered, and sucked dry. The residue isdissolved in 60 ml. of hot benzene, charcoaled, filtered through aheated funnel, and concentrated to a small volume to obtainS-(p-chlorophenyl)-2-piperidone (m.p. l7l .5-172.5C.).

EXAMPLE 2a 5-(o-Methylphenyl)-2-piperidone To 13 g. of methyl'y-cyano-y-(o-methylphenyl) butyrate and 0.5 g. of Raney Nickel is added15 ml. of ethanol. This is reacted at 150C. under 2,000 p.s.i. in ahydrogen atomosphere. The reaction mixture is filtered, rinsed withethanol and concentrated in vacuo to a solid residue. The residue isdissolved in benzene, filtered and concentrated to a volume of about 65ml. hot petroleum ether is then added to ml. total volume. This thenallowed to cool and the produce 5-(0- methylphenyl)-2-piperidone (m.p.l40.5-143C.) is collected.

EXAMPLE 2b When an equimolar amount of each of the 'y-cyano- 'y-(substituted phenyl)butyrate compounds of Tables II and IV, Example I,are used in place of methyl 7- cyano-y-(p-chlorophenyl)butyrate in theprocedures of Example 2, the corresponding 5-substituted phenyl-2-piperidone is formed. A representative list of these products is shownin Table I below.

TABLE I S-phenyI-Z-piperidone S-(p-fluorophenyl)-2-piperidone5-(o-fluorophenyl)-2-piperidone S-(m-fluorophenyl)-2-piperidone5-(o-chlorophenyl)-2-piperidone5-(m-chlorophenyl)-5-carboethoxy-2-piperidoneS-(p-methoxyphenyl)-2-piperidone5-(p-trifluoromethylphenyl)-2-piperidone5-(o-trifluoromethylphenyl)-2-piperidone5-(m-trifluoromethylphenyl)-2-piperidone5-(p-dimethylaminophenyl)-2-piperidoneS-(p-methylaminophenyl)-2-piperidone5-(p'biphenylyl)-5-methyl-2-piperidone S-(a-naphthyl)-2-piperidoneo-methylphenyl )-2-piperidone 2 ,-dichlorophenyl )-2-piperidonep-acetylphe nyl )-2-piperidone p-carbomethoxyphenyl )-5-phenyl-2-piperidone p-carboxyphenyl )-2-piperidone 5-(p-acetamidophenyl )-2-piperidone 5-(p-dimethylsulfamylphenyl)-2-piperidone 5 2-methyl-4-chlorophenyl)-2-piperidone 5-( 3 ,4 -dimethoxyphenyl )-2-piperidone 3-methyl-5-phenyl-2 piperidone 3-methyl-5 o-methylphenyl )piperidone 3-methyl-5p-chlorophenyl )piperidone 3-methyl-5 2 ,fi-dichlorophenyl)piperidone 3,4-dimethyl-5 o-methylphenyl)piperidone 3-dimethylam ino-S-phenyl-2-piperidone 3 -dimethylaminoethyl-5 -phenyl-2-piperidone4-phenyl-5 o-methylphenyl )-2-piperidone 3-phenyl-5 o-methylphenyl)-2-piperidone 3 ,4-dimethyl-5 -(p-chlorophenyl)-2-piperidone 3,4-dimethyl-5 o-methylphenyl )-2-piperidone 3-methyl-5 2,fi-dichlorophenyl )-2-piperidone 3-methyl-5-(p-methoxyphenyl)-2-piperidone 3 -methyl-5 2-methyl-4-chlorophenyl)-2-pipcridone 3 ,4-dimethyl-5 -(p-biphenylyl)-2-piperidone 3,4-dimethyl-5 o-chlorophenyl )-2-piperidone 3-methyl-5 3,4-dimethoxyphenyl )-2-piperidone EXAMPLE 3 S-(p-Chlorophenyl l-(2-propynyl)-2-piperidone To 5.23 g. of 5-(p-chlorophenyl)-2-piperidonedis- EXAMPLE 3b Following the procedure of Example 3 but substituting anequimolar amount of the reactant of Table I, Example 3a, in place ofl-bromo-2-propyneand an equimolar amount of the Z-piperidones of TableI', Example 2, and Example 7 and 9, in place ofS-(pchlorophenyl)-2-piperidone, the correspondingl-substituted-Z-piperidone products are obtained. A representative listof these products is shown in Table III below.

TABLE III 5 -phenyll 2-propenyl )-2-piperidone 5 -phenyll-benzyl-2-piperidone S-phenyl- 1 -methallyl-2-piperidone S-phenyll-benzoyl-2-piperidone 5 -phenyll 3-phenyl-2-propenyl )-2-piperidone 5-phenyll 2-butenyl )-2-piperidone EXAMPLE 3a When an equimolar amount ofthe reactants of Table I below are used in place of l'bromo-2-prop ynefollowing the procedure of Example 3, the corresponding 5-(p-chlorophenyl)-l-substituted-Z-piperidones of Table 11 below areprepared TABLE I methyl iodide Z-butenyl bromide 4-pentenyl bromidemethallyl bromide l-bromo-3-pentyne benzylchloride phenethyl bromidebenzoyl chloride acetyl chloride cyclopropane carbonyl chloridel-bromo-3-phenyl-2-propene B-diethylaminoethyl bromide TABLE II 5-phenyll -diethylaminoethyl-2-piperidone 5 o-methylphenyl)- l-benzoyl-2-pipcridone 5 o-methylphenyl)- l -acetyl-2-piperidone 5o-methylphenyl)-l -methallyl-2-piperidone 5 -(p-nitrophenyl l-benzoyl-2-piperidone 5-( p-nitrophenyl l -methallyl-2-piperidone 5p-nitrophenyl l p-chlorobenzoyl)-2-piperidone 5 2,6-dichlorophenyl l-methallyl-3-ch1oro-2- piperidone 5-( p-fl uorophenyl)- l-diethylaminoethyl-2- piperidone 5 -(p-acetamidophenyl l-phenethyl-2-piperidone 5-(p-dimethylaminophenyl)-1-benzoy1-2-piperidone 5-( p-methoxyphe'nyl 1-(p-chlorobenzoyl )-2- piperidone 5-( p-dimethylaminophenyl)- lp-chlorobenzoyl )-2- piperidone 5 a-naphthyl l -methyl-2-piperidone5-(o-methylphenyl)-1-acetyl-4-chloro-2-piperidone 5-( o-methylphenyl)- l-methyl-4-methyl-2-piperidone 5 -phenyl- 1-acetyl-3 -methyI-Z-piperidone 5 -phenyll -acetyl-3 -dimethylamino-2-piperidone 5p-nitrophenyl l -benzyl-3 ,4-dimethyl-2- piperidone 5-( p-fluorophenyl l2-butenyl )-3-carboxy-2- piperidone EXAMPLE 3cl-Phenyl-5-(o-tolyl)-2-piperidone To 0.025 m. of5-(o-tolyl)-2-piperidone dissolved in 5 p-chlorophenyl l -m ethyl-2-piperidone 5-(p-chlorophenyl)- l -(2-butenyl)-2-pip eridone5-(p-chlorophenyl)- l -(4-pentyl)-2-piperidone S-(p-chlorophenyl l-methallyl-2-piperidone 100 ml. of benzene is added 1.25 g. of sodiumhydride. The reaction mixture is heated to ca 45C. for 8 hours, and thenat room temperature for 15 hours. The mixture is then centrifuged andthe gel-like N-sodio compound dried in an Abderhalden. This is thenadded to 5 ml. of iodobenzene and 0.3 g. of copper metal and heatedrapidly to 120t2C. for 35 minutes and then allowed to cool slowly toroom temperature. Dry chloroform is then added to a volume of about 50ml., this is then allowed to stir, filtered and washed with chloroform.The chloroform is evaporated to dryness and the residue chromatographedon 300 g. of silica gel using 10-80 percent ether-petroleum ether toobtain 1- phenyl-5-(o-tolyl)2-piperidone.

In a similar manner the 5-aryl-2-piperidone of this invention may beconverted to the desired l-phenyl-S- aryI-Z-piperidone.

EXAMPLE 4 5-(o-Tolyl)-2-chloropyridine 2-Chloro-5-aminopyridine (5 g.)in 50 ml. of anhydrous toluene is added dropwise over one-half hour to150 ml. of toluene to which has just been added 8 ml. of isoamylnitrite, and which is held at 5055C. The mixture is heated to 75C. over2 hours. The solution is decanted from any tars which have precipitatedand the excess toluene is removed in vacuo. Distillation of the residueyields 5-(o-tolyl)-2-chloropyridine, and lesser amounts of the mandp-tolyl isomers.

EXAMPLE 4a Similarly, when the toluene in the above reaction is replacedby benzene, anisole, benzonitrile, xylene, nitrobenzene, fluorobenzene,benzotrifluoride, naphthylene, mand p-dichlorobenzenes, hydroquinone,dimethyl ether, veratrole or biphenyl, the corresponding2-chloro-5-arylpyridine is obtained. The products are mixtures of theisomeric arylpyridines and the isomers are separated by fractionaldistillation and/or column or vapor phase chromatography. In this waythere are obtained:

2-chloro-5-phenyl pyridines 2-chloro-5-(o-, mandp-methoxyphenyl)pyridines 2-chloro-5-(o-, mand p-cyanophenyl)pyridines2-chloro-5(o-, mand p-xylenyl)pyridines 2-chloro-5(o-, mandp-nitrophenyl)pyridines 2-chloro-5-(o-, mand p-fluorophenyl)pyridines2-chloro-5-(o-, mand p-trifluoromethyl)pyridines 2-chloro-5-(aandB-naphthyl)pyridines chlorophenyl)pryridines dimethoxyphenyl)pyridinesdimethoxyphenyl)pyridines 2chloro-5-(o-, mand p-biphenylyl)pyridinesEXAMPLE 4b mand p- 2-chloro-4-diethylaminoethyl-5 -(o-,

nitrophenyl)pyridine 2-chloro-3-phenyl-5 o-methylphenyl )pyridine2-chloro-3-carbom ethoxymethyl-S anaphthyl)pyridine EXAMPLE 55-(o-Tolyl-2[ lI-l]pyridone mand p- EXAMPLE 5a Similarly, when the othersubstituted 2-chloro-5- phenylpyridines from Examples 4a and 4b are usedin place of 2-chloro-5-(o-tolyl)pyridine, the corresponding 2-pyridoneis obtained. In this way there is obtained:

5-(o-, mand p-methylphenyl)-2[ lH]pyridones 5-(o-, mandp-methoxyphenyl)-2[ lI-Ilpyridones 5-(o-, mand p-nitrophenyl)-2[1H]pyridones 5-(o-, mand p-fluorophenyl)-2 lH]pyridones 5-(o-, mandp-trifluoromethyl)-2[1H]pyridones 5(aand B-naphthyl)-2[ ll-I]pyridonesdichlorophenyl)-2[ 1H1pyridones 5-(o,mm,po,o'- o,p'- m,mando,m'-dimethoxyphenyl)-2[ llflpyridones 5-(o-, mand p-biphenylyl)-2[lHlpyridones 3-methyl-5-phenyl-2[ lHlpyridone 4-methyl-5-phenyl-2[lI-I]pyridone 3-methyl-5-(o-, mand p-methylphenyl)2[lI-I] pyridone3-dimethylamino-5-(o-, mand p-methylphenyl)- 2[1H]apyridone4-diethylaminoethyl-5-(o-, mand p-nitrophenyl)- 2[ 1H1a-pyridone3-phenyl-5-(o-methylphenyl)-2[ lI-I]pyridone3-methyl-5-(a-naphthyl)-2[1H]pyridone EXAMPLE 6 5-(o-Tolyl)-2-piperidoneTo 0.01 mole of 5-(o-tolyl)-2-pyridone dissolved in 35 ml. of glacialacetic acid is added 0.2 g. of platinum oxide. The reaction mixture isreduced under hydrogen at room temperature and 40 p.s.i. It is thenfiltered and concentrated in vacuo and the residue chromatographed usingsilica gel, eluted with ether/petroleum ether. The product obtained is5-(o-tolyl)-2piperidone.

EXAMPLE 6a When an equimolar amount of the Z-pyridones from Example 5aare used in place of 5-(o-tolyl)-2-pyridone of Example 6, there isobtained the corresponding 2- piperidones. In this way there areobtained:

and o,m'-

3-methyl-5-(o-, mand p-methylphenyl)-2- piperidones3-dimethylamino-5-(o-, mand p-methylphenyD-Z- piperidones 3-phenyl-5(o-methylphenyl)-2-piperidones 3-methyl-5-(a-naphthyl)-2-piperidones Thefollowing representative examples are illustrate the interconversion orintroduction of functional groups at various stages of the preparationof the final products.

EXAMPLE 7 -(p-Nitrophenyl)-2-piperidone sucked dry and recrystallizedfrom dimethoxyethane to obtain 5-(p-nitrophenyl)-2-piperidone.

EXAMPLE 8 5- (p Aminophenyl)-2-piperidone 5-(p-Nitrophenyl)-2-piperidone(l g.) is reduced in 50 ml. of warm dioxane under a hydrogen atmospherein the presence of 0.3 g. of 5 percent palladium-on-carbon. The mixtureis filtered, washed with warm dioxane, and the combined filtratesconcentrated in vacuo to obtain S-(p-aminophenyl)-2-piperidone.

EXAMPLE 9 l-Methyl-5-(p-dimethylaminophenyl)2-piperidone EXAMPLE 10 5-(p-HydroxyphenyD-Zl lH]pyridone 5-(p-Methoxyphenyl)-2[ll-I]pyridone (2g.)is added to a stirred 10 g. portion of pyridine hydrochloride at 188C. Adry nitrogen atmosphere is maintained. The mixture is kept 20 minutes,allowed to cool, then added to 45 g. of ice. The crude product iscollected, dried, and chromatographed using methanol/methylene chloride(0l00%) to obtain 5-(p-hydroxyphenyl)2[l Hjpyridone.

EXAMPLE 1 l 5-(o-Methylphenyl )-2-thiopiperidone To 20.8 g. (0.11 mole)of 5-methylphenyl)-2- piperidone in ml. of dry pyridine is added 13 g.(0.058 mole) phosphorus pentasulfide suspended in 75 ml. of drypyridene. The reaction mixture is refluxed for one-half hour. Thepyridine is removed in vacuo and the residue pumped dry at roomtemperature for several hours. The residual black tar is extracted in aSoxhlet with 1,500 ml. benzene and the benzene then evaporated todryness. The residue is recrystallized from methanol to obtain5-(o-methylphenyl)-2- thiopiperidone.

EXAMPLE 12 When an equimolar amount of each of the two piperidones ofExample 2 are used in place of 5-(0- methylphenyl)-2-piperidone, thecorresponding 2- thiopiperidone is prepared.

5-(p-chlorophenyl)-2-thiopiperidone 5-phenyl-2-thiopiperidone5-(p-fluorophenyl)-2-thiopiperidone 5-(o-chlorophenyl)-2-thiopiperidone5-(m-chlorophenyl)-5-carboethoxy-2- thiopiperidone5-(p-methoxyphenyl)-2-thiopiperidone5-(p-trifluoromethylphenyl)-2-thiopiperidone5-(p-aminophenyl)-2-thiopiperidone5-(p-dimethylaminophenyl)-2-thiopiperidone5-(p-methylaminophenyl)-2-thiopiperidoneS-(p-biphenyl)-5-methyl-2-thiopiperidoneS-(p-nitrophenyl)-2-thiopiperidone S-(a-naphthyl)-2-thiopiperidone5-(o-methylphenyl)-2-thiopiperidone 5-(p-hydroxyphenyl)-2-thiopiperidone5-(2,6-dichlorophenyl)-2-thiopiperidone5-(p-carbomethoxyphenyl)-5-phenyl-2- thiopiperidone5-(p-carboxyphenyl)-2-thiopiperidone5-(p-dimethylsulfamylphenyl)-2-thiopiperidone 5 2-methyl-4-chlorophenyl)-2-thiopiperidone 5 3 ,4-dimethoxyphenyl)-2-thiopiperidone3methyl-5-phenyl-2-thiopiperidone3methyl-5-(o-methylphenyl)thiopiperidone3-methyl-5-(p-chlorophenyl)thiopiperidone3-methyl-5-(2,o-dichlorophenyl)thiopiperidone3,4-dimethyl-5-(o-methylphenyl)thiopiperidone3-chloro-5-(p-chlorophenyl)thiopiperidone3-amino-5-phenyl-2-thiopiperidone3-dimethylamino-5-phenyl-2-thiopiperidone3-dimethylaminoethyl-5-phenyl-2-thiopiperidone4-phenyl-5-(o-methylphenyl)-2-thiopiperidone3-phenyl-5-(o-methylphenyl)-2-thiopiperidone3-hydroxy-5-(p-hydroxyphenyl)-2-thiopiperidone 3-methyl-5-(p-nitrophenyl)-2-thiopiperidone3,4-dimethyl--(p-chlorophenyl)-2-thiopiperidone3,4-dimethyl-5-(o-methylphenyl)-2-thiopiperidone 3-methyl-5-(2,6-dichlorophenyl)-2-thiopiperidone3-methyl-5-(p-methoxyphenyl)-2-thiopiperidone3-methyl-5-(2-methyl-4-chlorophenyl)-2- thiopiperidone 3,4-dimethyl-5-(p-biphenylyl-Z-thiopiperidone3,4-dimethyl-5-(o-chlorophenyl )-2-thiopiperidone3-methyl-5-(3,4-dimethoxyphenyl)-2-thiopiperidone EXAMPLE l35-(p-Chlorophenyl)- l -benzyl-2-thiopiperidone To 27.9 g. of5-(p-chlorophenyl)-1-benzyl-2- piperidone in 75 ml. of dry pyridine isadded 13 g. (0.058 mole) phosphorus pentasulfide suspended in 75 ml. ofdry pyridine. The reaction mixture is refluxed for one-half hour. Thepyridine is removed in vacuo and the the residue pumped dry at roomtemperature for several hours. The residual black tar is extracted in aSoxhlet with 1,500 ml. benzene and the benzene then evaporated todryness. The residue is recrystallized from methanol to obtain5-(p-chlorophenyl)-l-benzyl- 2-thiopiperidone EXAMPLE 14 When anequimolar amount of each of the 2- piperidones of Table II, Example 3aand Table III, Example 3b, are used in place of the 5-(p-chlorophenyl)-l-benzyl-2-thiopiperidone in Example 13, then the corresponding2-thiopiperidone is prepared.

5-(p-chlorophenyl)-1-methyl-2-thiopiperidone S-(p-chlorophenyl l2-butenyl)-2-thiopiperidone 5 p-chlorophenyl)- l -(4-penteny1)-2-thiopiperid0ne S-(p-chlorophenyl)-1-methallyl-2-thiopiperidone5-(p-chlorophenyl)-l-(3-pentynyl)-2-thiopiperidone 5 -(p-chloropheny1 1-benzyl-2-thiopiperidone 5-(p-chlorophenyl)-l-phenethyl-2-thiopiperidone5-(p-chlorophenyl)-l-phenyl-2-thiopiperidone5-(p-chlorophenyl)-l-(3-phenyl-2-propenyl)-2- thiopiperidoneS-(p-chlorophenyl)-ldiethylaminoethyl-2- thiopiperidoneS-phenyl-l-(2-propenyl)-2-thiopiperidoneS-phenyl-1-benzyl-2-thiopiperidone 5-phenyll -methallyl-2-thiopiperidone5-phenyl-1-(3-phenyl-2-propenyl)-2-thiopiperidoneS-phenyl-l-(2-butenyl)-2-thiopiperidoneS-phenyl-ldiethylaminoethyl-2-thiopiperidone S-phenyll-phenyl-2-thiopiperidone 5-(o-methylphenyl)- l-methallyl-2-thiopiperidone5-(2,6-dichlorophenyl)-l-methallyl-3-chloro-2- thiopiperidone5-(p-fluorophenyl)-l-diethylaminoethyl-2- thiopiperidone S-(a-naphthyl l-methyl-2-thiopiperidone 5-(o-methylphenyl)-l -acetyl-4-chloro-2-thiopiperidone 5-(o-methylphenyl )-l -methyl-4-methyl-2- thiopiperidoneS-phenyll -acetyl-3-methyl-2-thiopiperidone S-phenyll-acetyl-3-dimethylamino-2- thiopiperidone5-(p-nitrophenyl)-1-benzyl-3,4-dimethyl-2- thiopiperidone 5-(o-methylphenyl)-l-phenyl-2thiopiperidone The invention is furtherdemonstrated by the following examples in which all parts are be weight.

EXAMPLE 15 A mixture of 250 parts of 5-(p-nitrophenyl)-2- piperidone and25 parts of lactose is granulated with suitable water, and to this isadded 100 parts of maize starch. The mass is passed through a 16 meshscreen. The granules are dried at a temperature below 60C. The drygranules are passed through a 16 mesh screen, and mixed with 3.8 partsof magnesium stearate. They are then compressed into tablets suitablefor oral administration.

The piperidone used in the foregoing example may be replaced by 25, 100or 500 parts of other piperidones or thiopiperidones of this inventionto produce tablets suitable for oral administration as anantiinflammatory, antipyretic and/or analgesic according to the methodof this invention.

EXAMPLE 16 A mixture of parts of 5-(p-ch1orophenyl)2- piperidone, 3parts of the calcium salt of lignin sulphonic acid, and 237 parts ofwater is ball-milled until the size of substantially all of theparticles of the piperidone is less than 10 microns. THe suspension isdiluted with a solution containing 3 parts of sodiumcarboxymethylcellulose and 0.9 parts of the butyl ester ofp-hydroxybenzoic acid in 300 parts of water. There is thus obtained anaqueous suspension suitable for oral administration for therapeuticpurposes.

EXAMPLE 17 A mixture of 250 parts of 5-(0-tolyl)-2-piperidone, 200 partsof maize starch and 30 parts of alginic acid is mixed with a sufficientquantity of 10 percent aqueous maize starch, and granulated. Thegranules are dried in a current of warm air and the dry granules arethen passed through a l6-mesh screen, mixed with 6 parts of magnesiumstearate and compressed into tablet form to obtain tablets suitable fororal administration.

EXAMPLE 18 A mixture of 500 parts of the thiopiperidone of Example 15,60 parts maize starch and 20 parts of gum acacia is granulated with asufficient quantity of water. The mass is passed through a l2-meshscreen and the granules are dried in a current of warm air. The drygranules are passed through a l6-mesh screen, mixed with 5 parts ofmagnesium stearate and compressed into tablet form suitable for oraladministration.

EXAMPLE l9 1. Tablets 10,000 scored tablets for oral use, eachcontaining 500 mg. of piperidone are prepared from the followingingredients:

The powered piperidone is granulated with a 4% w./v. aqueous solution ofmethylcellulose U.S.P. (1,500

cps). To the dried granules is added a mixture of the remainder of theingredients and the final mixture compressed into tablets of properweights.

2. Capsules 10,000 two-piece hard gelatin capsules for oral use, eachcontaining 250 mg. of piperidone is prepared from the followingingredients:

Gm. -(p-methoxyphenyl-Z-piperidone 2,500 Lactose, U.S.Pv 1,000 Starch,U.S.P. 300 Talc, U.S.P. 65 Calcium stearate 25 The powered piperidone ismixed with the starch-lactose mixture followed by the tale and calciumstearate. The final mixture is then encapsulated in the usual manner.Capsules containing 10, 25, 50 and 100 mg. of piperidone are alsoprepared by substituting 100, 250, 500 and 1,000 gm. for 2,500 gm. inthe above formula tion.

3. Soft elastic capsules One-piece soft elastic capsules for oral use,each containing 200 mg. of piperidone are prepared in the usual mannerby first dispersing the powdered active material in sufficient corn oilto render the material capsulatable.

4. Aqueous suspension An aqueous suspension for oral use containing ineach 5 ml., 1 gram of piperidone is prepared from the followingingredients:

S-phenyl-l-acetyl-2-piperidone gm 2,000 Methylparaben, U.S.P. gm 7.5Propylparaben U.S.P. gm 2.5 Saccharin sodium gm 12.5 Cyclamate sodium gm2.5 Glycerin ml 3,000 Tragacanth powder gm Orange oil flavor gm 10 F. D.and C. orange dye gm 7.5

Deionized water, q.s. to l0,000 mg.

What is claimed is:

1. A method of treating a condition exhibiting at least one of thesymptoms of pain, fever and inflammation which comprises theadministration to an animal or human of a therapeutically effectiveamount of a compound having the formula:

where R is hydrogen, loweralkyl, loweralkenyl, loweralky- 2. A methodaccording to claim 1 where R is hydrogen, loweralkyl, or acyl; W ishydrogen or loweralkyl; and W and Y are each hydrogen, nitro, halogen,loweralkyl or haloloweralkyl. =3. A method according to claim 2 whereinthe compound is selected from the group consisting of5-phenyl-2-piperidone, 5-(o-chlorophenyl)-2-piperidone, 5-(p-chlorophenyl)-2-piperidone, 5-(o-fluorophenyl)-2- piperidone,5-(o-methylphenyl)-2-piperidone, S-(mtrifluoro-methylphenyl)-2-piperidone and 3-methyl-5-phenyl-Z-piperidone.

4. A method according to claim 3 wherein the compound is5-phenyl-2-piperidone.

5. A method according to claim 3 wherein the compound is5-(o-chlorophenyl)-2-piperidone.

6. A method according to claim 3 wherein the compound is5-(p-chlorophenyl)-2-piperidone.

7. A method according to claim 3 wherein the compound is5-(o-fluorophenyl)-2-piperidone.

8. A method according to claim 3 wherein the compound is5-(o-methylphenyl)-2-piperidone.

9. A method according to claim 3 wherein the compound is5-(m-trifluoromethylphenyl)-2-piperidone.

10. A method according to claim 3 wherein the compound is3-methyl-5-phenyl-2-piperidone.

11. A tablet, capsule or suppository preparation in dosage unit foradministration to obtain an antiinflammatory, anti-pyretic and analgesiceffect, comprising, per dosage unit, an inert pharmaceutical carrier andan effective non-toxic amount within the range from about 5 milligramsto about 5 grams of a compound of the formula:

where R is hydrogen, lowweralkyl, lower alkenyl, loweral- -kynyl,arloweralkyl, arloweralkenyl, aryl, acyl, or

diloweralkylaminoloweralkyl;

W is hydrogen, halogen, loweralkyl, amino, diloweralkylamino,diloweralkylaminoloweralkyl, aryl, carboxyloweralkyl,carboloweralkoxyloweralkyl or hydroxy;

X and Y are each hydrogen,'loweralkyl, halogen, hydroxy, loweralkoxy,'haloloweralkyl, aryl, nitro, amino, acylamino, acyl, carboxy,carboloweralkoxy, diloweralkylsulfamyl, loweralkylamino, ordiloweralkylamino.

.12. A preparation according to claim H where R is hydrogen, loweralkylor acyl; W is hydrogen or loweralkyl; and X and Y are each hydrogen,nitro, halogen, loweralkyl or haloloweralkyl.

113. A preparation according to claim 12 wherein the compound isselected from the group consisting of 5'- phenyI-Z-piperidone,5-(o-chlorophenyl)-2- piperidone, 5-(p-chlorophenyl)-2-piperidone, 5-(0-fluorophenyl)-2-piperidone, 5-(o-methylphenyl)-2- piperidone,S-m-trifluoro-methylphenyl)-2-piperidone, and3-methyl-S-phenyl-2-piperidone.

14. A preparation according to claim 13 wherein the 18. A preparationaccording to claim 13 wherein the compound is -phenyl-2-piperidone.compound is 5-(o-methylphenyl)-2-piperidone.

15. A preparation according to claim 13 wherein the 19. A preparationaccording to claim 13 wherein the compound is 5(o-chlorophenyl)-2-piperidone. compound is y p y 16. A preparationaccording to claim 13 wherein the 5 p p compound i 5 hl h 2- i i 20. Apreparation according to claim 13 wherein the compound is3-methyl-5-phenyl-2-piperidone.

17. A preparation according to claim 13 wherein the compound isS-(o-fluorophenyl)-2-piperidone.

2. A method according to claim 1 where R is hydrogen, loweralkyl, oracyl; W is hydrogen or loweralkyl; and W and Y are each hydrogen, nitro,halogen, loweralkyl or haloloweralkyl.
 3. A method according to claim 2wherein the compound is selected from the group consisting of5-phenyl-2-piperidone, 5-(o-chlorophenyl)-2-piperidone,5-(p-chlorophenyl)-2-piperidone, 5-(o-fluorophenyl)-2-piperidone,5-(o-methylphenyl)-2-piperidone,5-(m-trifluoro-methylphenyl)-2-piperidone and3-methyl-5-phenyl-2-piperidone.
 4. A method according to claim 3 whereinthe compound is 5-phenyl-2-piperidone.
 5. A method according to claim 3wherein the compound is 5-(o-chlorophenyl)-2-piperidone.
 6. A methodaccording to claim 3 wherein the compound is5-(p-chlorophenyl)-2-piperidone.
 7. A method according to claim 3wherein the compound is 5-(o-fluorophenyl)-2-piperidone.
 8. A methodaccording to claim 3 wherein the compound is5-(o-methylphenyl)-2-piperidone.
 9. A method according to claim 3wherein the compound is 5-(m-trifluoromethylphenyl)-2-piperidone.
 10. Amethod according to claim 3 wherein the compound is3-methyl-5-phenyl-2-piperidone.
 11. A tablet, capsule or suppositorypreparation in dosage unit for administration to obtain anantiinflammatory, anti-pyretic and analgesic effect, comprising, perdosage unit, an inert pharmaceutical carrier and an effective non-toxicamount within the range from about 5 milligrams to about 5 grams of acompound of the formula:
 12. A preparation according to claim 11 where Ris hydrogen, loweralkyl or acyl; W is hydrogen or loweralkyl; and X andY are each hydrogen, nitro, halogen, loweralkyl or haloloweralkyl.
 13. Apreparation according to claim 12 wherein the compound is selected fromthe group consisting of 5-phenyl-2-piperidone,5-(o-chlorophenyl)-2-piperidone, 5-(p-chlorophenyl)-2-piperidone,5-(o-fluorophenyl)-2-piperidone, 5-(o-methylphenyl)-2-piperidone,5-m-trifluoro-methylphenyl)-2-piperidone, and3-methyl-5-phenyl-2-piperidone.
 14. A preparation according to claim 13wherein the compound is 5-phenyl-2-piperidone.
 15. A preparationaccording to claim 13 wherein the compound is5-(o-chlorophenyl)-2-piperidone.
 16. A preparation according to claim 13wherein the compound is 5-(p-chlorophenyl)-2-piperidone.
 17. Apreparation according to claim 13 wherein the compound is5-(o-fluorophenyl)-2-piperidone.
 18. A preparation according to claim 13wherein the compound is 5-(o-methylphenyl)-2-piperidone.
 19. Apreparation according to claim 13 wherein the compound is5-(m-trifluoromethylphenyl)-2-piperidone.
 20. A preparation according toclaim 13 wherein the compound is 3-methyl-5-phenyl-2-piperidone.